2. Academic Validation
  3. 5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression

5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression

  • Bioorg Med Chem. 2015 Nov 1;23(21):7069-78. doi: 10.1016/j.bmc.2015.09.025.
Ju-Hee Kang 1,  Zheng Ting 1,  Mi-ran Moon 1,  Jung-Seon Sim 1,  Jung-Min Lee 1,  Kyung-Eun Doh 2,  Sunhye Hong 2,  Minghua Cui 2,  Sun Choi 2,  Hyeun Wook Chang 3,  Hea-Young Park Choo 4,  Mijung Yim 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
  • 2 College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
  • 3 College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
  • 4 College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: hypark@ewha.ac.kr.
  • 5 College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea. Electronic address: myim@soomyung.ac.kr.
PMID: 26432605 DOI: 10.1016/j.bmc.2015.09.025
Abstract

5-Lipoxygenase synthesizes leukotrienes from arachidonic acid. We developed three novel 5-LO inhibitors having a benzoxazole scaffold as a potential anti-osteoclastogenics. They significantly suppressed RANKL-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, one compound, K7, inhibited the bone resorptive activity of osteoclasts. The anti-osteoclastogenic effect of K7 was mainly attributable to reduction in the expression of NFATc1, an essential transcription factor for osteoclast differentiation. K7 inhibited osteoclast formation via ERK and p38 MAPK, as well as NF-κB signaling pathways. K7 reduced lipopolysaccharide (LPS)-induced osteoclast formation in vivo, corroborating the in vitro data. Thus, K7 exerted an inhibitory effect on osteoclast formation in vitro and in vivo, properties that make it a potential candidate for the treatment of bone diseases associated with excessive bone resorption.

Keywords

5-Lipoxygenase; Benzoxazole scaffold; Lipopolysaccharide (LPS)-induced osteoclast formation; NFATc1; RANKL-induced osteoclast formation.

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